Osteoporosis, a disease characterized by the systemic loss of bone mass and strength resulting in fragility fractures, is rapidly poised to become a major public health threat in the United States. Osteoporosis results from imbalances in bone remodeling, a process characterized by osteoblast-mediated bone synthesis and osteoclast-mediated bone resorption. Because osteoporosis is fairly asymptomatic, and is often detected only after the patient has sustained significant bone erosion, therapies aimed at restoring the eroded bone are equally important as those that target bone resorption. However, unlike the highly efficient repertoire of anti- resorptive drugs that form the mainstay of the current anti-osteoporosis therapy, drugs that stimulate bone formation remain largely underdeveloped. Hence there is a critical need for novel therapeutic targets that will stimulate osteoblast-mediated bone accrual together with the inhibition of osteoclastic bone resorption. Our preliminary studies identify Ca2+/calmodulin (CaM)-dependent protein kinase kinase 2 (CaMKK2) as one such target as its inhibition positively impacts anabolic pathways and negatively impacts catabolic pathways of bone remodeling. Mice null for CaMKK2 possess enhanced trabecular bone mass in their long bones, along with significantly higher numbers of osteoblasts and fewer multinuclear osteoclasts. Moreover, its inhibition offers protection from ovariectomy-induced and age-associated osteoporosis in mice. The proposed studies will enable us to define the precise mechanism by which CaMKK2 regulates osteoblast and osteoclast differentiation and devise potential strategies of its inhibition in the treatment of osteoporosis. Development of CaMKK2 inhibition as a new generation therapeutic target that promotes robust bone mass accrual while inhibiting resorption will represent a major breakthrough in anti-osteoporosis treatment.